1-46671959-C-G

Variant names:

• chr1-46671959-C-G
• rs770465669
• NM_001145474.4:c.25C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001145474.4(TEX38):​c.25C>G​(p.Arg9Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000719 in 1,390,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R9C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: TEX38 NM_001145474.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.09
• Publications: 0 publications found

Genes affected

TEX38 (HGNC:29589): (testis expressed 38) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ATPAF1 (HGNC:18803): (ATP synthase mitochondrial F1 complex assembly factor 1) This gene encodes an assembly factor for the F(1) component of the mitochondrial ATP synthase. This protein binds specifically to the F1 beta subunit and is thought to prevent this subunit from forming nonproductive homooligomers during enzyme assembly. Alternatively spliced transcript variants have been identified. [provided by RefSeq, Aug 2011]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05183217).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TEX38	NM_001145474.4	c.25C>G	p.Arg9Gly	missense_variant	Exon 1 of 2	ENST00000334122.5	NP_001138946.1
TEX38	NM_001300863.2	c.-59C>G		5_prime_UTR_variant	Exon 1 of 2		NP_001287792.1
TEX38	NM_001300864.2	c.-53C>G		5_prime_UTR_variant	Exon 1 of 2		NP_001287793.1
TEX38	XM_011541421.4	c.41-914C>G		intron_variant	Intron 1 of 1		XP_011539723.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TEX38	ENST00000334122.5	c.25C>G	p.Arg9Gly	missense_variant	Exon 1 of 2	1	NM_001145474.4	ENSP00000455854.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.19e-7 AC: 1 AN: 1390206 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 684706

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31392

American (AMR) AF: 0.00 AC: 0 AN: 34882

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24650

East Asian (EAS) AF: 0.0000281 AC: 1 AN: 35542

South Asian (SAS) AF: 0.00 AC: 0 AN: 77846

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49104

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5522

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1073718

Other (OTH) AF: 0.00 AC: 0 AN: 57550

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	6.3
DANN	Benign	0.70
DEOGEN2	Benign	0.0047	T
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.052	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.1
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.60	N
Sift	Benign	0.58	T
Sift4G	Benign	0.47	T
Polyphen		0.010	B
Vest4		0.14
MVP		0.36
GERP RS		1.1
PromoterAI		-0.0084	Neutral
Varity_R		0.089
gMVP		0.034
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs770465669; hg19: chr1-47137631;